Can Hormone Therapy Cut Alzheimer's Risk?

Some women with a gene linked to Alzheimer's disease may have rapidly aging body cells, even when they are in apparently good health, a small study suggests.

On the other hand, researchers found, there were no signs of accelerated cell aging when those same women were on hormone replacement therapy.

It's not clear what can be made of the findings for now, said senior study author Dr. Natalie Rasgon, a professor of psychiatry and behavioral sciences at the Stanford University School of Medicine, in California.

Most important, no one can say whether hormone therapy could lower the risk of Alzheimer's, or any other disease, in women who carry the gene variant -- known as ApoE4.

"This is an interesting study that raises more questions than answers," Rasgon said. "It opens avenues for further research."

Everyone carries two copies of the ApoE gene, which is involved in transporting cholesterol and other fats through the bloodstream. There are three main versions, or variants, of the ApoE gene. People who carry at least one copy of the E4 variant have a higher-than-average risk of developing Alzheimer's. About 25 to 30 percent of the population carries an E4 variant, according to the U.S. National Institute on Aging.

In the new study, reported Feb. 13 in the journal PLoS One, Rasgon's team recruited 63 healthy postmenopausal women who were using hormone therapy -- either estrogen alone or a combination of estrogen and progesterone. They randomly assigned the women to either stick with their hormone therapy or stop it for two years.

Of the whole group, 24 were ApoE4 carriers.

The researchers then looked at changes in the women's telomeres -- which are protective caps at the ends of chromosomes. Telomeres shorten as people age, and also because of oxidative stress and inflammation from environmental stressors, such as cigarette smoke.

Overall, Rasgon's team found, women with the E4 gene were much more likely to have substantial shortening in their telomere length. On average, they showed a decades' worth of telomere shortening in just two years -- a sign of accelerated cell aging.

That was the average, at least. When the researchers looked at E4 carriers who'd remained on hormone therapy, they saw no significant telomere shortening.

In contrast, among women who did not carry the E4 gene, there was no evidence that hormone therapy had a protective effect against telomere shortening.

"This suggests that hormone therapy may be protective in carriers," Rasgon said. "But the key word is 'may.''"

And why would hormones have such an effect? Rasgon said this study cannot answer that. There is animal research suggesting that estrogen might directly influence telomere length -- or affect it indirectly by, for example, lowering chronic inflammation in the body.

But no one knows if any of that animal research translates to humans, Rasgon said.

Peter Davies, an Alzheimer's researcher not connected to the study, also urged caution in interpreting the results.

For one, they are based on small numbers of women, said Davies, who directs the Litwin Zucker Research Center for the Study of Alzheimer's Disease at the Feinstein Institute for Medical Research in Manhasset, N.Y.

He also noted that the researchers looked at averages: Not all E4 carriers on hormones seemed protected against telomere shortening. By the same token, carriers who were off of hormone therapy did not always show accelerated shortening.

Davies agreed that the findings raise questions for future studies. But for now, there's no practical use for women. One reason is that most people have no idea if they carry the E4 gene. Testing is only done in the research setting -- not the doctor's office.

The same is true of telomere length. "You can't go out and have your telomere length checked," Davies pointed out.

Then there is the whole issue of hormone therapy for women. A decade ago, a large U.S. study found that women on estrogen/progesterone therapy had increased risks of blood clots, heart attack, stroke, and breast cancer.

And right now, hormones are recommended only when a woman has severe hot flashes or other menopausal symptoms. Even then, experts say, the therapy should be given at the lowest dose and for the shortest time possible.

"It's a complicated issue," Davies noted.

According to study author Rasgon, yet another question is whether middle-aged men with the E4 variant also show relatively speedy telomere shortening. "That's for future, larger studies," she said.

For now, both Rasgon and Davies stressed that people should remember that the E4 gene signals only a relatively increased risk of Alzheimer's. Carrying it does not mean you are destined to develop the memory-robbing disease. And people with other variants can and do develop Alzheimer's.

"In fact, the majority of Alzheimer's disease patients do not carry the E4 (variant)," Davies said.

It's estimated that 40 percent of people who develop Alzheimer's after age 60 have a copy of the E4 gene.

The study was funded by the U.S. National Institutes of Health and the Robert Wood Johnson Foundation Health and Society Scholars Program.

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